The invention relates to a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole (CCT), and also intermediates used therein.
2-Chloro-5-chloromethyl-1,3-thiazole is a useful intermediate in the preparation of pesticides or of pharmaceutical products.
The literature discloses a multiplicity of highly varied processes for the preparation of CCT. For example, EP 0 260 560 and EP 0 446 913 describe the preparation of CCT by reaction of allyl isothiocyanate or an allyl isothiocyanate substituted with a leaving group with a chlorinating agent, and EP 0 763 531 describes the reaction of 2-chloroallyl isothiocyanate with a chlorinating agent. These processes have disadvantages in that, for example, several by-products occur in the first variant, which cause CCT prepared in this way to have a low purity, and the starting material in the second variant can only be obtained at high cost. Further, a considerable excess of chlorinating agents must be used and the process must be operated at high dilution. Also, exact control of the reaction temperature is necessary and the stable intermediates formed in the course of the reaction have to be converted exothermically to the desired final product in an additional reaction step. EP 0 794 180 describes the preparation of CCT from 1,3-dichloropropene and a thiocyanate salt via 3-chloro-1-isothiocyanate-1-propene as an improvement.
Other variants, such as the process according to EP 0 775 700, in which the CCT is prepared via 2-amino-5-methylthiazole by means of diazotization and subsequent chlorination, also have the disadvantage that CCT is contaminated by a multiplicity of by-products, which are very difficult or impossible to remove and lead to high yield losses.
It is an object of the invention to provide novel processes which facilitate the preparation of the CCT in high purity and yield.
The invention accordingly provides a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole, which comprises reacting a compound of the formula 
in which X is Cl, xe2x80x94OR, xe2x80x94SR or xe2x80x94NR2, where R is H or a suitable protecting group; Y is H or Cl; and Z is Cl or O,
the compounds of the formula (I) having a maximum of one double bond between C* and Cxe2x80x3 or between Cxe2x80x3 and Z, with the proviso that the bond between Cxe2x80x3 and Z is a double bond when Z is O and is a single bond when Z is Cl,
a) where X and Y are Cl and Z is O either
a1) first with thiocyanate to give a compound of the formula 
and then with an acid/Rxe2x80x2OH or acid/orthoester mixture, where Rxe2x80x2 is C1 to C6-alkyl, to give the compound of the formula 
or first converting the compound of the formula (I) to the acetal and then reacting with thiocyanate to give the compound of the formula (III), then converting it to 2-chloro-5-chloromethyl-1,3-thiazole,
or
a2) with thiourea to give; a mixture of compounds of the formulae 
and, after basic cleavage to give the corresponding thiol or amine, converting to 2-chloro-5-chloromethyl-1,3-thiazole by Sandmeyer diazotization and optional reaction with a chlorinating agent
or
b) where X is OR, SR or NR2, and R is H or a suitable protecting group, Y is Cl and Z is O, with thiourea to give a compound of the formula 
and then substituting the amino group by a chlorine atom by Sandmeyer reaction, and obtaining 2-chloro-5-chloromethyl-1,3-thiazole by chlorination and optional ether cleavage or
c) where X is OR, SR or NR2, and R is H or a suitable protecting group, Y is Cl and Z is O, with ammonium dithiocarbamate or ammonium thiocarbamate to give the compound 
and, if necessary, converting the radical X into the corresponding radical OH, SH or NH2 by removal of the protecting group, and then obtaining 2-chloro-5-chloromethyl-1,3-thiazole by reaction with suitable chlorinating agents, or
d) where X, Y and Z are all Cl, and the compound contains no double bonds,
with thiourea to give a thiazolidine of the formula 
and then dehydrogenating and diazotizing to give 2-chloro-5-chloromethyl-1,3-thiazole or
e) where X and Z are both Cl and Y is H, and the compound contains a double bond between C* and Cxe2x80x3, with an oxidizing agent to convert it to the corresponding epoxide, which
e1) is converted directly to 2-amino-5-chloromethyl-1,3-thiazole using thiourea in a suitable solvent and/or is converted to the compound of the formula (V), where X is ORxe2x80x2, and Rxe2x80x2 is H or C1-C6-alkyl, and is then converted to 2-chloro-5-chloromethyl-1,3-thiazole by diazotization and, if necessary, ether cleavage and/or chlorination, or
e2) similarly to c), is converted to 2-chloro-5-chloromethyl-1,3-thiazole by reaction with ammonium dithiocarbamate or ammonium thiocarbamate.
According to the invention, CCT is prepared by starting from a compound of the formula (I) in which X is Cl, xe2x80x94OR, xe2x80x94SR or xe2x80x94NR2, where R is H or a protecting group; Y is H or Cl and Z is Cl or O, the compounds of the formula (I) having a maximum of one double bond between C* and Cxe2x80x3 or between Cxe2x80x3 and Z, with the proviso that the bond between Cxe2x80x3 and Z is a double bond when Z is O and is a single bond when Z is Cl.
In the formula (I), the radical R is H or a protecting group. Useful protecting groups include all groups suitable for protection of the oxygen, sulfur or nitrogen radical. These include C1-C6-alkyl groups, such as methyl, ethyl, propyl, i-butyl, t-butyl, hexyl, or the phthalimide group.
Variant a):
In variant a), X and Y are both chlorine and Z is oxygen, so that 2,3-dichloropropanal is used as starting compound of the formula (I).
2,3-Dichloropropanal is easily accessible, for example by chlorination of acrolein in dichloromethane. According to the invention, the conversion of the aldehyde to CCT can be carried out by the variants a1) or a2).
Variant a1):
Variant a1) involves aldehyde first being reacted with sodium or ammonium thiocyanate to give the compound of the formula (II). The thiocyanate can be used in an equimolar quantity, or in excess or deficiency based on the aldehyde. Thiocyanate is preferably used in deficiency. The reaction takes place in a suitable solvent. Suitable solvents include all customary organic solvents, for example carboxylic acids having from 1 to 6 carbon atoms, such as formic acid, acetic acid, propionic acid, etc.; halogenated aliphatic and aromatic hydrocarbons, such as methylene chloride, trichloromethane, trichloroethylene, carbon tetrachloride, chlorobenzene, dichlorobenzene etc.; alcohols, such as methanol, ethanol, propanol, t-butanol, etc.; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol monomethyl ether, tetrahydrofuran, dioxane etc; ketones, such as acetone, methyl ethyl ketone, methyl i-butyl ketone, cyclohexanone etc.; amides, such as N,N-dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, etc.; sulfoxides, such as dimethyl sulfoxide, etc. and nitriles, such as acetonitrile, propionitrile, etc.
Further useful solvents include water or solvent/water mixtures.
It can also be advantageous to add a phase transfer catalyst to the solvent. The preferred quantity of added phase transfer catalyst is in the range from 0.1 to 15 mol %. Useful phase transfer catalysts include crown ethers, quaternary ammonium salts, such as tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, and also quaternary phosphonium salts.
Preferred solvents in the variant a1) are C1-C3-carboxylic acids, nitriles, chlorinated aliphatic hydrocarbons and amides. Most preferred are acetic acid, acetonitrile, dimethylformamide and a methylene chloride/crown ether mixture.
The temperature is in the range from 10 to 150xc2x0 C., more preferably from 15 to 130xc2x0 C., most preferably from 20 to 80xc2x0 C.
The compound of the formula (II) is novel and therefore likewise forms part of the subject matter of the invention.
The compound of the formula (II) is then converted to the acetal of the formula (III) by addition of an acid/Rxe2x80x2OH or acid/orthoester mixture at from 10 to 100xc2x0 C.
Useful acids include HCl and p-toluenesulfonic acid. Useful alcohols Rxe2x80x2OH include C1-C6-alcohols, such as methanol or ethanol and propanol. Preference is given to ethanol.
Useful orthoesters include alkyl orthoformates, such as methyl orthoformate or ethyl orthoformate.
The compound of the formula (III) is novel and therefore likewise forms part of the subject matter of the invention.
However, the aldehyde can also first be converted to the corresponding acetal. This conversion is carried out in a similar fashion to the above process. The acetal is then converted to the compound of the formula (III) by reaction with sodium or ammonium thiocyanate, again in a similar fashion to the above process.
The compound of the formula (III) is then converted to 2-chloro-5-chloromethyl-1,3-thiazole by suitable steps, such as rearrangements, alcohol elimination, or ether cleavage, reaction with a chlorinating agent etc.
It is further possible to convert the aldehyde of the formula (II) directly to 2-chloro-5-chloromethyl-1,3-thiazole by means of suitable steps.
Variant a2):
Variant a2) first involves reaction of the aldehyde of the formula (I) with thiourea to give a mixture of the compounds N-[[5-(2-aminothiazol)yl]-methyl]thiourea and [5-(2-aminothiazol)yl]methylthioformamidine of the formulae (IVa) and (IVb), which occur in the form of their hydrochloride salts. From 0.8 to 2 equivalents of thiourea are preferably used. The reaction takes place in one of the solvents listed under variant a1). Preference is given to ketones, such as methyl i-butyl ketone or acetone, or alcohols, such as methanol, ethanol or butanol.
The reaction temperature is in the range from 15xc2x0 C. and the boiling point of the solvent used.
The compounds of the formulae (IVa) and (IVb), and their hydrochloride salts are also novel and therefore likewise form part of the subject matter of the invention.
The conversion to CCT takes place by basic cleavage in the corresponding thiol or amine, subsequent Sandmeyer diazotization and, if necessary, chlorination.
The Sandmeyer diazotization takes place under the reaction conditions customary for this type of reaction, for example using inorganic or organic nitrites, preferably using sodium nitrite or t-butyl nitrite in HCl (e.g. aqueous HCl) or mixtures of HCl and an organic polar solvent, such as acetonitrile, in the optional presence of a copper halide catalyst.
Useful chlorinating agents include those compounds that have reactive chloride atoms under the reaction conditions. These are, for example, Cl2, sulfuryl chloride, PCl5, PCl3, POCl3 etc.
The operation of the chlorination reaction generally takes place by the usual methods.
Variant b):
In variant b), X is a radical xe2x80x94OR, xe2x80x94SR or xe2x80x94NR2 where R is H or suitable protecting group; Y is Cl and Z is oxygen.
The corresponding aldehyde is reacted with thiourea to give the compound of the formula (V). Thiourea is used in an equimolar quantity, or in excess or deficiency. Thiourea is preferably used in a small deficiency based on the aldehyde. The amino group is then exchanged for a chlorine atom by a Sandmeyer reaction in a similar fashion to variant a2)
In order to obtain CCT, the ether group is then optionally cleaved and the corresponding radical substituted by a chlorine atom. The cleavage and chlorination are likewise carried out in a similar fashion to a2).
Variant c):
In variant c), X is OR, SR or NR2 where. R is H or suitable protecting group, Y is Cl and Z is O.
The corresponding compound of the formula (I) is either reacted with ammonium dithiocarbamate or with ammonium thiocarbamate to give the compound of the formula (VIa) or (VIb) respectively.
Useful solvents again include those listed under variant a1). Preference is given to amides, alcohols or nitriles. The reaction is more preferably carried out in DMF, methanol or ethanol, or acetonitrile.
The reaction temperature is in the range from 0xc2x0 C. to the boiling point of the solvent used.
If necessary, the radical X is cleaved by known methods for protecting group cleavage, which gives the corresponding radical OH, SH or NH2. Depending on the protecting group, the cleavage takes place, for example, under acidic, basic or hydrogenolytic conditions.
The further conversion to give CCT takes place by reaction with suitable chlorinating agents in a similar fashion to variant a2).
Variant d)
In variant d), X, Y and Z are all chlorine atoms and the compound has no double bond. The starting compound is therefore 1,2,3-trichloropropane, which is reacted with thiourea to give the thiazolidine of the formula (VII). Again, thiourea can be used in an equimolar quantity, or in a less or greater than stoichiometric quantity based on trichloropropane. Useful solvents are those listed under variant a1). The reaction temperatures are in the range from 0xc2x0 C. to the boiling point of the solvent used.
Thiazolidine is then dehydrogenated by addition of customary oxidizing agents for aromatization (customary dehydrating agents), such as sulfur, chloranil, DDQ, platinum oxide etc., under the customary conditions for dehydrogenations.
Finally, the Sandmeyer diazotization to give CCT is carried out in a similar fashion to variant a2) under the customary reaction conditions for diazotization reactions.
Variant e):
In variant e), X and Z are chlorine atoms, Y is H and the compound has a double bond between C* and Cxe2x80x3. The starting compound is therefore 1,3-dichloro-1-propene, which is converted to 2-chloro-3-chloromethyl-oxirane under conditions disclosed in the literature by a suitable oxidizing agent, such as a peroxy acid, an acid/H2O2 mixture, inorganic or organic peroxides, or hydroperoxides.
Useful solvents include nitriles, such as acetonitrile, or chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, methylene chloride, 1,2-dichloroethane or chlorobenzene.
Useful peroxy acids include, for example, peracetic acid, m-chloroperbenzoic acid etc.
According to variant e1), the oxirane or epoxide obtained is then converted to the compound of the formula (V) by thiourea in a suitable solvent in a similar fashion to the other variants. Useful solvents are those listed under variant a1). Useful solvents of the variant e1) are alcohols, in particular methanol, ethanol and t-butanol, ketones, in particular acetone, nitriles, in particular acetonitrile, ethers, in particular tetrahydrofuran, dimethoxyethane, amides, in particular N-methylpyrrolidone, water or mixtures of water, in particular acetone/H2O or acetonitrile/H2O mixtures. Mixtures of an alcohol with other solvents, for example with dichloromethane, can also be used. Solvent mixtures with an alcohol, in particular methanol, and dichloromethane are therefore also preferred. When a solvent mixture is used, it can be advantageous to additionally add a suitable base, such as a trialkylamine.
Depending on the choice of solvent, 2-amino-5-chloromethyl-1,3-thiazole is formed directly or the compound of the formula (V) with identical R and Rxe2x80x2 is first formed or also mixtures of 2-amino-5-chloromethyl-1,3-thiazole and 2-amino-5-alkoxymethyl-1,3-thiazole and/or 2-amino-5-hydroxymethyl-1,3-thiazole. The compound of the formula (V) where X is ORxe2x80x2 is formed in particular when an alcohol is used as solvent.
The compound obtained by the reaction with thiourea or the mixture of the above compounds is then converted to CCT by diazotization and, if necessary, ether cleavage and/or chlorination. The sequence of these steps may vary.
Similar to the other variants, the exchange of the amino group for a chlorine atom takes place by diazotization.
If the compound of the formula (V) where X is ORxe2x80x2 or a mixture as described above is obtained in the first step, the ether group, if necessary, must be cleaved and a chlorination carried out in a similar fashion to the previously described variants, in order to obtain CCT. The ether cleavage., and also the chlorination, can take place before, after the diazotization or sometimes also simultaneously with the diazotization.
It is also possible to carry out the ether cleavage and the chlorination in a single step. The C1-C6-alkoxyl group of the radical ORxe2x80x2 is preferably replaced directly, i.e. in a single step, by Cl, by reaction with POCl3 or with acetyl chloride, optionally in combination with a Lewis acid, such as ZnCl2, AlCl3 or BCl3, or with dry HCl in combination with a Lewis acid, such as ZnCl2, AlCl3 or BCl3.
A further alternative to the previously described chlorination steps to replace the C1-C6-alkoxyl group or the hydroxyl group of the radical ORxe2x80x2 by a chlorine atom is the reaction of the corresponding thiazole with thionyl chloride.
In variant e2), oxirane or epoxide obtained is reacted with ammonium dithiocarbamate or ammonium thiocarbamate to give CCT in a similar fashion to variant c), which makes any cleavage of the radical X required in variant e1) unnecessary.
The isolation and workup of the CCT prepared takes place, depending on the chosen preparation variant, by customary methods, such as extraction, distillation, etc.